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Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B

List of authors.
  • Pratima Chowdary, M.D.,
  • Susan Shapiro, Ph.D.,
  • Mike Makris, M.D.,
  • Gillian Evans, M.B., Ch.B.,
  • Sara Boyce, M.D.,
  • Kate Talks, M.D.,
  • Gerard Dolan, M.D.,
  • Ulrike Reiss, M.D.,
  • Mark Phillips, M.Sc.,
  • Anne Riddell, M.Sc.,
  • Maria R. Peralta, M.D.,
  • Michelle Quaye, B.Sc.,
  • David W. Patch, M.D.,
  • Edward Tuddenham, M.D.,
  • Allison Dane, Ph.D.,
  • Marie Watissée, M.Sc.,
  • Alison Long, M.D.,
  • and Amit Nathwani, M.B., Ch.B., Ph.D.

Abstract

Background

FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B.

Methods

Download a PDF of the Research Summary.

In this multicenter, open-label, phase 1–2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, as assessed by factor IX levels at week 26.

Results

Ten patients received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84×1011 vg, 6.40×1011 vg, 8.32×1011 vg, or 1.28×1012 vg. After receiving the infusion, all the patients had dose-dependent increases in factor IX levels. At a median follow-up of 27.2 months (range, 19.1 to 42.4), sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. As of the data-cutoff date (September 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had a level of 260%. Of the reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events. Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high factor IX levels.

Conclusions

Sustained factor IX levels in the normal range were observed with low doses of FLT180a but necessitated immunosuppression with glucocorticoids with or without tacrolimus. (Funded by Freeline Therapeutics; ClinicalTrials.gov numbers, NCT03369444 and NCT03641703; EudraCT numbers, 2017-000852-24 and 2017-005080-40.)

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Phase 1–2 Trial of Gene Therapy for Hemophilia B
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Funding and Disclosures

Supported by Freeline Therapeutics.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the trial patients and their families; the staff members at each trial site; the members of the independent data and safety monitoring committee (Prof. Andy Baker, Dr. Ri Liesner, and Prof. Len Seymour); the members of the trial steering committee (Prof. George Dickson, Prof. Massimo Pinzani, and Prof. Sian Harding); the trial management group (whose members are listed in the Supplementary Appendix); Mr. John Morris for assistance with trial activities; Dr. Gerard Short for assistance with the trial design; Syneos Health for assistance with data analysis; Drs. Nancy Griffith and Patrick Flight of Freeline Therapeutics for their assistance in development of the manuscript; and Oxford PharmaGenesis for administrative assistance and formatting of previous versions of the figures.

Author Affiliations

From the Katharine Dormandy Haemophilia and Thrombosis Centre (P.C., M.P., A.R., M.R.P., E.T., A.N.), Health Services Laboratory, Sonic Healthcare (A.R.), and the Department of Hepatology and Liver Transplantation (D.W.P.), Royal Free Hospital, University College London (P.C., M.P., M.Q., A.N.), Guy’s and St. Thomas’ Hospital (G.D.), and Wstats (M.W.), London, Oxford University Hospitals Foundation Trust, Oxford NIHR Biomedical Research Centre, and Oxford University, Oxford (S.S.), the University of Sheffield, Sheffield (M.M.), East Kent Hospitals NHS University Foundation Trust, Canterbury (G.E.), University Hospital Southampton, Southampton (S.B.), Newcastle upon Tyne Hospitals NHS Trust, Newcastle (K.T.), and Freeline Therapeutics, Stevenage (A.D., A.N.) — all in the United Kingdom; St. Jude Children’s Research Hospital, Memphis, TN (U.R.); and Freeline Therapeutics, New York (A.L.).

Dr. Nathwani can be contacted at or at Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, Pond St., London NW3 2QG, United Kingdom.

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